BackgroundVentral striatal cholinergic interneurons (ChIs) play a central role in basal ganglia function by regulating associative learning and reward processing. In the nucleus accumbens (NAc), ChIs regulate glutamatergic, dopaminergic,... more
BackgroundVentral striatal cholinergic interneurons (ChIs) play a central role in basal ganglia function by regulating associative learning and reward processing. In the nucleus accumbens (NAc), ChIs regulate glutamatergic, dopaminergic, and GABAergic neurotransmission. However, it is unclear how ChIs orchestrate the control of these neurotransmitters to determine the excitability of medium spiny neurons (MSNs) expressing either dopamine D1 or D2 receptors. Additionally, the effects of binge alcohol drinking on ChIs-mediated modulation of glutamatergic synaptic transmission in NAc MSNs are also undefined.MethodsWe optogenetically stimulated ChIs while recording evoked and spontaneous excitatory postsynaptic currents (sEPSCs) in D1- and D2-MSN of ChAT.ChR2.eYFPxDrd1.tdtomato mice. To determine the effect of ChIs on mouse behavior and alcohol consumption, we implanted ChAT.ChR2.eYFP mice with fiber optic cannulas and stimulated ChIs while mice were allowed to drink 20% alcohol using t...
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The nucleus accumbens (NAc) is a forebrain region mediating the positive-reinforcing properties of drugs of abuse, including alcohol. It receives glutamatergic projections from multiple forebrain and limbic regions such as the prefrontal... more
The nucleus accumbens (NAc) is a forebrain region mediating the positive-reinforcing properties of drugs of abuse, including alcohol. It receives glutamatergic projections from multiple forebrain and limbic regions such as the prefrontal cortex (PFCx) and basolateral amygdala (BLA), respectively. However, it is unknown how NAc medium spiny neurons (MSNs) integrate PFCx and BLA inputs, and how this integration is affected by alcohol exposure. Because progress has been hampered by the inability to independently stimulate different pathways, we implemented a dual wavelength optogenetic approach to selectively and independently stimulate PFCx and BLA NAc inputs within the same brain slice. This approach functionally demonstrates that PFCx and BLA inputs synapse onto the same MSNs where they reciprocally inhibit each other pre-synaptically in a strict time-dependent manner. In alcohol-naïve mice, this temporal gating of BLA-inputs by PFCx afferents is stronger than the reverse, revealing...
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Dopamine (DA) signaling is critical for movement, motivation, and addictive behavior. The neuronal GTPase, Rit2, is enriched in DA neurons (DANs), binds directly to the DA transporter (DAT), and is implicated in several DA-related... more
Dopamine (DA) signaling is critical for movement, motivation, and addictive behavior. The neuronal GTPase, Rit2, is enriched in DA neurons (DANs), binds directly to the DA transporter (DAT), and is implicated in several DA-related neuropsychiatric disorders. However, it remains unknown whether Rit2 plays a role in either DAergic signaling and/or DA-dependent behaviors. Here, we leveraged the TET-OFF system to conditionally silence Rit2 in Pitx3IRES2-tTA mouse DANs. Following DAergic Rit2 knockdown (Rit2-KD), mice displayed an anxiolytic phenotype, with no change in baseline locomotion. Further, males exhibited increased acute cocaine sensitivity, whereas DAergic Rit2-KD suppressed acute cocaine sensitivity in females. DAergic Rit2-KD did not affect presynaptic TH and DAT protein levels in females, nor was TH was affected in males; however, DAT was significantly diminished in males. Paradoxically, despite decreased DAT levels in males, striatal DA uptake was enhanced, but was not due...
Research Interests: Pharmacology, Neuroscience, Addiction, Biology, Neuropsychopharmacology, and 15 moreMedicine, Anxiety, Nucleus Accumbens, Dopamine, Striatum, Substance Abuse and Addiction, Gene Delivery, Dopamine Transporter, ANXIETY, Nervous System, Excitability, Psychology and Cognitive Sciences, Medical and Health Sciences, Rit, and Addictive behavior
The nucleus accumbens (NAcc) may play a major role in opiate dependence, and central NMDA receptors are reported to influence opiate tolerance and dependence. Therefore, we investigated the effects of the selective μ-opioid receptor... more
The nucleus accumbens (NAcc) may play a major role in opiate dependence, and central NMDA receptors are reported to influence opiate tolerance and dependence. Therefore, we investigated the effects of the selective μ-opioid receptor agonist [d-Ala2-N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO) on membrane properties of rat NAcc neurons and on events mediated by NMDA and non-NMDA glutamate receptors, using intracellular recording in a brain slice preparation. Most NAcc neurons showed a marked inward rectification (correlated with Cs+- and Ba2+-sensitive inward relaxations) when hyperpolarized, as well as a slowly depolarizing ramp with positive current pulses. Superfusion of DAMGO did not alter membrane potential, input resistance, or the inward relaxations. In the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) used to block non-NMDA glutamate receptors and bicuculline to block GABAAreceptors, EPSPs evoked by local stimulation displayed characteristics of an NMDA component: (1) long...
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In a study of a possible substrate underlying morphine addiction, we examined NMDA receptor-mediated synaptic transmission of core nucleus accumbens neurons after chronic morphine treatment, using intracellular recording in a slice... more
In a study of a possible substrate underlying morphine addiction, we examined NMDA receptor-mediated synaptic transmission of core nucleus accumbens neurons after chronic morphine treatment, using intracellular recording in a slice preparation of rat. We evoked pharmacologically isolated NMDA EPSCs by local stimulation and elicited inward currents by NMDA superfusion. In control slices, Mg2+and phorbol 12,13-diacetate (PDAc), a protein kinase C activator, strongly inhibited and increased, respectively, NMDA EPSC amplitudes. The PDAc effects were likely postsynaptic because PDAc enhanced the currents evoked by superfused NMDA to the same extent that it did the NMDA EPSCs. Chronic morphine treatment significantly decreased NMDA EPSC amplitudes and the sensitivity of NMDA EPSCs to Mg2+and PDAc, as well as the kinetics of the decay (inactivation rate) of the EPSCs (from 97 ± 2.5 msec in untreated rats to 78.7 ± 1.8 msec in slices from treated rats). One week after withdrawal, the Mg2+an...
Research Interests: Neuroscience, Chemistry, Kinetics, Neurotransmission, Enzyme Inhibitors, and 15 moreMedicine, Nucleus Accumbens, Magnesium, Animals, Male, Morphine, Narcotics, Long Term Effect, Phorbol ester, Glutamate Receptor, Excitatory Postsynaptic Potentials, NMDA receptor, Intracellular recording, Protein Kinase C, and Medical and Health Sciences
RNA interference (RNAi) is a straightforward approach to study gene function from thecellular level toanimal behavior. Although RNAi-mediated gene knockdown has become essentially routine in neuroscience over the past ten years,... more
RNA interference (RNAi) is a straightforward approach to study gene function from thecellular level toanimal behavior. Although RNAi-mediated gene knockdown has become essentially routine in neuroscience over the past ten years, off-target effects of short hairpin RNAs (shRNAs) should be considered as the proper choice of control shRNA is critical in order to perform meaningful experiments. Luciferase shRNA (shLuc), targeting firefly luciferase, and scrambled shRNAs (shScrs) have been widely used as controls for vertebrate cell research. However, thorough validation of control shRNAs has not been made to date. Here, we performed thorough physiological and morphological studies against control shRNAs in mouse hippocampal CA1 pyramidal neurons. As expected, all control shRNAs exhibited normal basal synaptic transmission and dendritic morphology. However, to our surprise, shLuc exerted severe off-target effects on voltage-gated ion channel function, while the shScr had no detectable ch...
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Binge alcohol drinking, a behavior characterized by rapid repeated alcohol intake, is most prevalent in young adults and is a risk factor for excessive alcohol consumption and alcohol dependence. Although the alteration of synaptic... more
Binge alcohol drinking, a behavior characterized by rapid repeated alcohol intake, is most prevalent in young adults and is a risk factor for excessive alcohol consumption and alcohol dependence. Although the alteration of synaptic plasticity is thought to contribute to this behavior, there is currently little evidence that this is the case. We used drinking in the dark (DID) as a model of binge alcohol drinking to assess its effects on spike timing-dependent plasticity (STDP) in medium spiny neurons (MSNs) of the core nucleus accumbens (NAc) by combining patch-clamp recordings with calcium imaging and optogenetics. After 2 weeks of daily alcohol binges, synaptic plasticity was profoundly altered. STDP in MSNs expressing dopamine D1 receptors shifted from spike-timing-dependent long-term depression (tLTD), the predominant form of plasticity in naive male mice, to spike-timing-dependent long-term potentiation (tLTP) in DID mice, an effect that was totally reversed in the presence of ...
Research Interests: Neuroscience, Chemistry, Long Term Potentiation, Medicine, Signal Transduction, and 15 moreNucleus Accumbens, Dopamine, Optogenetics, Mice, Animals, Male, Neuronal Plasticity, Dopamine Receptors, Binge drinking, Neural pathways, Action Potentials, Organic Chemicals, NMDA receptor, Psychology and Cognitive Sciences, and Medical and Health Sciences
Research Interests: Physiology, Biophysics, Chemistry, Life Sciences, Calcium, and 15 moreMedicine, Experimental Physiology, Cell Culture, Patch-clamp and imaging techniques, Histamine, Humans, Smooth muscle, Health Science, Potassium, Medical Physiology, Membrane Potential, Voltage Clamp, Interleukin, Airway Inflammation, and Smooth muscle cell
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Voltage-gated sodium channels are essential for generating the initial rapid depolarization of neuronal membrane potential during action potentials (APs) that enable cell-to-cell communication, the propagation of signals throughout the... more
Voltage-gated sodium channels are essential for generating the initial rapid depolarization of neuronal membrane potential during action potentials (APs) that enable cell-to-cell communication, the propagation of signals throughout the brain, and the induction of synaptic plasticity. Although all brain neurons express one or several variants coding for the core pore-forming sodium channel α subunit, the expression of the β (β1-4) auxiliary subunits varies greatly. Of particular interest is the β4 subunit, encoded by the Scn4b gene, that is highly expressed in dorsal and ventral (i.e., nucleus accumbens - NAc) striata compared to other brain regions, and that endows sodium channels with unique gating properties. However, its role on neuronal activity, synaptic plasticity, and behaviors related to drugs of abuse remains poorly understood. Combining whole-cell patch-clamp recordings with two-photon calcium imaging in Scn4b knockout (KO) and knockdown mice, we found that Scn4b altered t...
ABSTRACT
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It is widely accepted that long-lasting changes of synaptic strength in the nucleus accumbens (NAc), a brain region involved in drug reward, mediate acute and chronic effects of alcohol. However, our understanding of the mechanisms... more
It is widely accepted that long-lasting changes of synaptic strength in the nucleus accumbens (NAc), a brain region involved in drug reward, mediate acute and chronic effects of alcohol. However, our understanding of the mechanisms underlying the effects of alcohol on synaptic plasticity is limited by the fact that the NAc receives glutamatergic inputs from distinct brain regions (e.g., the prefrontal cortex (PFCx), the amygdala and the hippocampus), each region providing different information (e.g., spatial, emotional and cognitive). Combining whole-cell patch-clamp recordings and the optogenetic technique, we examined synaptic plasticity, and its regulation by alcohol, at cortical, hippocampal and amygdala inputs in fresh slices of mouse tissue. We showed that the origin of synaptic inputs determines the basic properties of glutamatergic synaptic transmission, the expression of spike-timing dependent long-term depression (tLTD) and long-term potentiation (LTP) and long-term potent...
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We compared the effects of different metabotropic glutamate receptor (mGluR) agonists on pharmacologically isolated N-methyl-D-aspartate-excitatory postsynaptic currents (NMDA-EPSCs) in core nucleus accumbens neurons using conventional... more
We compared the effects of different metabotropic glutamate receptor (mGluR) agonists on pharmacologically isolated N-methyl-D-aspartate-excitatory postsynaptic currents (NMDA-EPSCs) in core nucleus accumbens neurons using conventional intracellular recording in untreated and morphine-treated rats. The rats were treated by s.c. implantation of two morphine pellets and studied over a 3- to 6-day period. This model is known to exhibit opiate tolerance and dependence. We elicited NMDA-EPSCs by stimulating locally in the presence of the alpha-amino-3-hydroxy-5-methly-4-isoxazolepropionic acid/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) and the gamma-aminobutyric acid receptor antagonist bicuculline (15 microM). We found that trans-1-aminocyclopentane-1,3-decarboxylic acid, an agonist of group 1 and 2 mGluRs, decreased NMDA-EPSC areas (time-integrals) in a dose-dependent manner (1-10 microM) in slices taken from untreated rats. This inhibitory effect was ...
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Tolerance is a well described component of alcohol abuse and addiction. The large conductance voltage- and Ca(2+)-gated potassium channel (BK) has been very useful for studying molecular tolerance. The influence of association with the β4... more
Tolerance is a well described component of alcohol abuse and addiction. The large conductance voltage- and Ca(2+)-gated potassium channel (BK) has been very useful for studying molecular tolerance. The influence of association with the β4 subunit can be observed at the level of individual channels, action potentials in brain slices, and finally, drinking behavior in the mouse. Previously, we showed that 50 mm alcohol increases both α and αβ4 BK channel open probability, but only α BK develops acute tolerance to this effect. Currently, we explore the possibility that the influence of the β4 subunit on tolerance may result from a striking effect of β4 on kinase modulation of the BK channel. We examine the influence of the β4 subunit on PKA, CaMKII, and phosphatase modulation of channel activity, and on molecular tolerance to alcohol. We record from human BK channels heterologously expressed in HEK 293 cells composed of its core subunit, α alone (Insertless), or co-expressed with the β...
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Alcohol is a fast acting molecule that alters behavior within a few minutes of absorption. Its rapid behavioral impact suggests early action on ion channels. Of all voltage-gated potassium ion channels, BK channels, a subcategory of... more
Alcohol is a fast acting molecule that alters behavior within a few minutes of absorption. Its rapid behavioral impact suggests early action on ion channels. Of all voltage-gated potassium ion channels, BK channels, a subcategory of potassium channels characterized by their large unitary conductance, and by their capacity of being activated synergistically by membrane potential and intracellular free calcium, are unique due to their high sensitivity to alcohol. In this review, we discuss BK channels structure and function, and how they help us understand the various ways BK channel mediates alcohol's effects on neuronal function and on behavior in the striatum.
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The hypocretins (hcrt1 and hcrt2), also known as orexins, are two neuropeptides derived from the same precursor, expressed in a few thousand cells in the lateral hypothalamus. Hypocretin-containing cells project throughout the brain,... more
The hypocretins (hcrt1 and hcrt2), also known as orexins, are two neuropeptides derived from the same precursor, expressed in a few thousand cells in the lateral hypothalamus. Hypocretin-containing cells project throughout the brain, including ascending projections to the olfactory bulb and cerebral cortex, through the medial septum and the nucleus accumbens. Here, we have studied the interactions of the hypocretins with different neurotransmitters by patch clamp recording of acutely dissociated cells from the nucleus accumbens. Application of hcrt1 or hcrt2 decreased postsynaptic NMDA currents, enhanced GABA currents but did not affect glycine-activated conductances. Our results strongly suggest that the hypocretin peptides may be inhibitory peptides, probably via binding hcrt receptor 2.
Research Interests: Electrophysiology, Drug interactions, Patch-clamp and imaging techniques, Nucleus Accumbens, Neuropeptides, and 15 moreCerebral Cortex, Animals, Male, Sleep, Synaptic Transmission, NMDA, Rats, Olfactory Bulb, Glycine, Lateral Hypothalamus, Action Potentials, Patch Clamp, Medial Septum, G Protein Coupled Receptors, and Medical and Health Sciences
We recorded intracellularly from core nucleus accumbens (NAcc) neurons in brain slices to study the regulation by metabotropic glutamate receptors (mGluRs) of pharmacologically isolated N-methyl--aspartate-mediated excitatory postsynaptic... more
We recorded intracellularly from core nucleus accumbens (NAcc) neurons in brain slices to study the regulation by metabotropic glutamate receptors (mGluRs) of pharmacologically isolated N-methyl--aspartate-mediated excitatory postsynaptic currents (NMDA-EPSCs). Monosynaptic NMDA-EPSCs, evoked by local stimulation, were isolated by superfusion of the non-NMDA and gamma-aminobutyric acid-A (GABAA) receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM) and bicuculline (15 microM), respectively. Trans-1-aminocyclopentane-1,3-decarboxylic acid (trans-ACPD; 50 microM), a nonspecific group 1 and 2 mGluR agonist, had no effect on resting membrane potential (RMP) or input resistance of NAcc neurons. However, it consistently decreased NMDA-EPSC areas (time integrals) dose dependently (1-100 microM; EC50 = 8 microM) and reversibly. The specific group 1 mGluR agonists quisqualate (1-4 microM) and (RS)-3, 5-dihydroxyphenylglycine (DHPG; 100 microM) did not mimic the trans-A...
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In the present work, we have studied the effects of systemic morphine on the electrophysiological properties of ventromedial medulla (VMM) neurons in the awake, freely moving rat. By means of a chronically implanted single-unit recording... more
In the present work, we have studied the effects of systemic morphine on the electrophysiological properties of ventromedial medulla (VMM) neurons in the awake, freely moving rat. By means of a chronically implanted single-unit recording device, a drug delivery catheter, and the use of controlled innocuous and noxious cutaneous stimuli, we were able to study precisely the spontaneous and evoked VMM neuronal activities. We have particularly focused our attention upon the VMM "multimodal, multireceptive" units, excited by non-noxious and noxious stimuli (VMM MULT ON), which we have already determined as the neuronal class potentially involved in nociceptive processes at VMM level. We found that morphine (3 mg/kg, i.v.) does not affect the spontaneous activity of these neurons whereas their responses to noxious heat are strongly attenuated (70%), over a prolonged period (about 2 hr) associated with an increase in the response latency. This action of morphine appears to be pha...
Research Interests: Electrophysiology, Pain, Drug delivery, Control system, Animals, and 15 moreSpinal Cord, The, Neurons, Morphine, Wakefulness, Rats, Narcotics, Neuronal Activity, Mechanism of action, Single Unit Recording, Dorsal Horn, Spontaneous Activity, Motor activity, Psychology and Cognitive Sciences, and Medical and Health Sciences
Histone methyltransferases specific for the histone H3-lysine 9 residue, including Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e are associated with repressive chromatin remodeling and expressed in adult brain, but potential effects on... more
Histone methyltransferases specific for the histone H3-lysine 9 residue, including Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e are associated with repressive chromatin remodeling and expressed in adult brain, but potential effects on neuronal function and behavior remain unexplored. Here, we report that transgenic mice with increased Setdb1 expression in adult forebrain neurons show antidepressant-like phenotypes in behavioral paradigms for anhedonia, despair, and learned helplessness. Chromatin immunoprecipitation in conjunction with DNA tiling arrays (ChIP-chip) revealed that genomic occupancies of neuronal Setdb1 are limited to <1% of annotated genes, which include the NMDA receptor subunit NR2B/Grin2B and other ionotropic glutamate receptor genes. Chromatin conformation capture and Setdb1-ChIP revealed a loop formation tethering the NR2B/Grin2b promoter to the Setdb1 target site positioned 30 kb downstream of the transcription start site. In hippocampus and ventral striatum,...
Research Interests: Animal Behavior, Fear, Affect, Hippocampus, Humans, and 15 moreMice, Animals, Neurons, Chromatin, Chromatin Immunoprecipitation, Age Factors, Food Preferences, Exploratory Behavior, Maze Learning, Gene Expression Regulation, Motor activity, Electroshock, Excitatory Postsynaptic Potentials, Avoidance Learning, and Medical and Health Sciences
non-NMDA-EPSP amplitudes with reversal of this effect by naloxone and the m-selective antagonist (Cys2-Tyr3-Orn5- Pen7)-somatostatinamide (CTOP). To assess a postsynaptic action of DAMGO, we superfused slices with tetrodotoxin and evoked... more
non-NMDA-EPSP amplitudes with reversal of this effect by naloxone and the m-selective antagonist (Cys2-Tyr3-Orn5- Pen7)-somatostatinamide (CTOP). To assess a postsynaptic action of DAMGO, we superfused slices with tetrodotoxin and evoked inward currents by local application of glutamate ago- nists. Surprisingly, 0.1-1 mM DAMGO markedly enhanced the NMDA currents (with reversal by CTOP) but reduced the non- NMDA currents. At higher
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Research Interests: Psychology, Cognitive Science, Electrophysiology, Schizophrenia, Neuropharmacology, and 15 moreGene expression, Patch-clamp and imaging techniques, Glutamate, Female, Animals, Xenopus laevis, Oocytes, Voltage Clamp, Neurosciences, Clozapine, Subunit, Glutamate Receptor, NMDA receptor, Antipsychotic agents, and In Vitro Techniques
In the awake, freely moving rat we showed, by means of single-unit recordings and antidromic spinal cord activation, that at the ventromedial medulla level, in these particular experimental conditions, the &#39;multimodal,... more
In the awake, freely moving rat we showed, by means of single-unit recordings and antidromic spinal cord activation, that at the ventromedial medulla level, in these particular experimental conditions, the &#39;multimodal, multireceptive&#39; units excited by auditory, cutaneous non-noxious and noxious stimuli are possibly involved in a spinal descending control system. These neurons were back-fired from the medial part of the lateral funiculus, hence they probably projected to the dorsal and intermediate horn of the cord, and not to the ventral horn, which emphasizes a role in the control of nociception. Due to their convergent properties, these units are probably involved in nonspecific aspects of nociception such as alertness or stress.
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Neurons are highly differentiated and polarized cells, whose various functions depend upon the compartmentalization of ion channels. The rat hypothalamic-neurohypophysial system (HNS), in which cell bodies and dendrites reside in the... more
Neurons are highly differentiated and polarized cells, whose various functions depend upon the compartmentalization of ion channels. The rat hypothalamic-neurohypophysial system (HNS), in which cell bodies and dendrites reside in the hypothalamus, physically separated from their nerve terminals in the neurohypophysis, provides a particularly powerful preparation in which to study the distribution and regional properties of ion channel proteins. Using electrophysiological and immunohistochemical techniques, we characterized the large-conductance calcium-activated potassium (BK) channel in each of the three primary compartments (soma, dendrite, and terminal) of HNS neurons. We found that dendritic BK channels, in common with somatic channels but in contrast to nerve terminal channels, are insensitive to iberiotoxin. Furthermore, analysis of dendritic BK channel gating kinetics indicates that they, like somatic channels, have fast activation kinetics, in contrast to the slow gating of terminal channels. Dendritic and somatic channels are also more sensitive to calcium and have a greater conductance than terminal channels. Finally, although terminal BK channels are highly potentiated by ethanol, somatic and dendritic channels are insensitive to the drug. The biophysical and pharmacological properties of somatic and dendritic versus nerve terminal channels are consistent with the characteristics of exogenously expressed alphabeta1 versus alphabeta4 channels, respectively. Therefore, one possible explanation for our findings is a selective distribution of auxiliary beta1 subunits to the somatic and dendritic compartments and beta4 to the terminal compartment. This hypothesis is supported immunohistochemically by the appearance of distinct punctate beta1 or beta4 channel clusters in the membrane of somatic and dendritic or nerve terminal compartments, respectively.
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Although there is now evidence of a role for N-methyl-D-aspartate (NMDA) receptors in nucleus accumbens (NAcc) neurons in the effects of chronic opiate treatment, the cellular and molecular mechanisms underlying this phenomenon are still... more
Although there is now evidence of a role for N-methyl-D-aspartate (NMDA) receptors in nucleus accumbens (NAcc) neurons in the effects of chronic opiate treatment, the cellular and molecular mechanisms underlying this phenomenon are still unclear. Therefore, we studied the effects of chronic morphine on the pharmacological and biophysical properties of NMDA receptors in freshly isolated medium spiny neurons from NAcc. We found that chronic morphine treatment did not alter the affinity for NMDA receptor agonists such as glutamate, homoquinolinic acid, and NMDA, but decreased the affinity of glycine, the allosteric NMDA receptor coagonist, from 2.24 +/- 0.15 microM to 5.1 +/- 1.45 microM. Chronic morphine treatment also altered the affinity of two noncompetitive NMDA receptor antagonists, 7-chloro-kynurenic acid and ifenprodil. However, morphine had no effect on a third antagonist, D-(-)-2-amino-5-phosphonopentanoic acid. Single-exponential fits of desensitized NMDA current tails gave tau values ranging from 0.5 to 4 s in neurons from both control and morphine-treated rats. However, a shift to the left of the distribution of tau values after morphine treatment revealed that NMDA current desensitization rate was accelerated in a majority of NAcc neurons. Taken together with our recent molecular studies, our data are consistent with a shift away from NMDA receptor subunit (NR) NR2B and 2C function toward increased NR2A subunit expression or function after chronic morphine, a process that could alter excitability and integrative properties and may represent a neuroadaptation of NAcc medium spiny neurons underlying morphine dependence.
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The nucleus accumbens is a forebrain region responsible for drug reward and goal-directed behaviors. It has long been believed that drugs of abuse exert their addictive properties on behavior by altering the strength of synaptic... more
The nucleus accumbens is a forebrain region responsible for drug reward and goal-directed behaviors. It has long been believed that drugs of abuse exert their addictive properties on behavior by altering the strength of synaptic communication over long periods of time. To date, attempts at understanding the relationship between drugs of abuse and synaptic plasticity have relied on the high-frequency long-term potentiation model of T.V. Bliss &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp; T. Lømo [(1973) Journal of Physiology, 232, 331-356]. We examined synaptic plasticity using spike-timing-dependent plasticity, a stimulation paradigm that reflects more closely the in vivo firing patterns of mouse core nucleus accumbens medium spiny neurons and their afferents. In contrast to other brain regions, the same stimulation paradigm evoked bidirectional long-term plasticity. The magnitude of spike-timing-dependent long-term potentiation (tLTP) changed with the delay between action potentials and excitatory post-synaptic potentials, and frequency, whereas that of spike-timing-dependent long-term depression (tLTD) remained unchanged. We showed that tLTP depended on N-methyl-d-aspartate receptors, whereas tLTD relied on action potentials. Importantly, the intracellular calcium signaling pathways mobilised during tLTP and tLTD were different. Thus, calcium-induced calcium release underlies tLTD but not tLTP. Finally, we found that the firing pattern of a subset of medium spiny neurons was strongly inhibited by dopamine receptor agonists. Surprisingly, these neurons were exclusively associated with tLTP but not with tLTD. Taken together, these data point to the existence of two subgroups of medium spiny neurons with distinct properties, each displaying unique abilities to undergo synaptic plasticity.
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Research Interests: Cognitive Science, Electrophysiology, Pain, Electroencephalography, Brain, and 10 moreAnimals, Anesthesia, Neurons, Rats, Rat, Nociception, Neurosciences, Pentobarbital, Methohexital, and Nociceptors(Animals, Anesthesia, Neurons, Rats, Rat, Nociception, Neurosciences, Pentobarbital, Methohexital, and Nociceptors)
(Animals, Anesthesia, Neurons, Rats, Rat, Nociception, Neurosciences, Pentobarbital, Methohexital, and Nociceptors)
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Research Interests: Intellectual Disability, Mental Retardation, Humans, Mutation, Mice, and 11 moreAnimals, Peptides, American, Synaptic Transmission, Molecular cloning, Genotype, DNA mutational analysis, Autistic disorder, Psychology and Cognitive Sciences, reverse transcriptase polymerase chain reaction, and Medical and Health Sciences
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Research Interests: Neuroscience, Kinetics, Calcium, Immunohistochemistry, Nucleus Accumbens, and 15 moreCell line, Humans, Animals, Male, Ethanol, Dendrites, Neurons, Rats, Action potential, Action Potentials, Electric Conductivity, Patch Clamp, Single Channel, Psychology and Cognitive Sciences, and Medical and Health Sciences
Dopamine, a key neurotransmitter mediating the rewarding properties of drugs of abuse, is widely believed to exert some of its effects by modulating neuronal activity of nucleus accumbens (NAcc) medium spiny neurons (MSNs). Although its... more
Dopamine, a key neurotransmitter mediating the rewarding properties of drugs of abuse, is widely believed to exert some of its effects by modulating neuronal activity of nucleus accumbens (NAcc) medium spiny neurons (MSNs). Although its effects on synaptic transmission have been well documented, its regulation of intrinsic neuronal excitability is less understood. In this study, we examined the cellular mechanisms of acute dopamine effects on core accumbens MSNs evoked firing. We found that 0.5µM A-77636 and 10µM quinpirole, dopamine D1 (DR1s) and D2 receptor (D2Rs) agonists, respectively, markedly inhibited MSN evoked action potentials. This effect, observed only in about 25% of all neurons, was associated with spike-timing-dependent (STDP) long-term potentiation (tLTP), but not long-term depression (tLTD). Dopamine inhibited evoked firing by compromising subthreshold depolarization, not by altering action potentials themselves. Recordings in voltage-clamp mode revealed that all MS...